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      Levodopa-Carbidopa Intestinal Gel in Advanced Parkinson'd Disease: Final 12-Month, Open-Label Results

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          Abstract

          Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. l-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces l-dopa-plasma–level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day “off” time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, “on” time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% ( P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% ( P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% ( P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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          Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.

          C Warren Olanow, C Warren Olanow, Moneeb Othman … (2014)
          Levodopa is the most effective therapy for Parkinson's disease, but chronic treatment is associated with the development of potentially disabling motor complications. Experimental studies suggest that motor complications are due to non-physiological, intermittent administration of the drug, and can be reduced with continuous delivery. We aimed to assess efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In our 12-week, randomised, double-blind, double-dummy, double-titration trial, we enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centres in Germany, New Zealand, and the USA. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube, and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomisation was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. We assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. We assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. We assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. This study is registered with ClinicalTrials.gov, numbers NCT00660387 and NCT0357994. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. Continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications. Benefits noted with intestinal gel delivery were of a greater magnitude than were those obtained with medical therapies to date, and our study is, to our knowledge, the first demonstration of the benefit of continuous levodopa delivery in a double-blind controlled study. AbbVie. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications.

            C Warren Olanow, Jose Obeso, Fabrizio Stocchi (2006)
            Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease. Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications. The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications. The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.
            Article 0 comments Cited 113 times – based on 0 reviews     Review now
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              Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease.

              R Constantinescu, Ylva Nilsson, N Dizdar … (2005)
              To compare daytime intraduodenal levodopa/carbidopa infusion as monotherapy with individually optimized conventional combination therapies in patients with advanced Parkinson disease (PD) for motor fluctuations and quality of life (QoL). Twenty-four patients with motor fluctuations and dyskinesia were studied in a randomized crossover design to compare individualized conventional treatment and intraduodenal infusion of a levodopa/carbidopa gel for 3 + 3 weeks. Video scoring of motor function was assessed by blinded assessors on a global Treatment Response Scale from -3 to 0 to +3 (from severe "off" to "on" to "on" with severe dyskinesia). Patient self-assessment of motor performance and QoL was done using an electronic diary. Median percentage of ratings in a functional "on" interval (-1 to +1) was increased from 81 to 100% by infusion therapy (p < 0.01). This improvement was accompanied by a decrease in "off" state (p < 0.01) and no increase in dyskinesia. Median Unified Parkinson's Disease Rating Scale score decreased from 53 to 35 in favor of infusion (p < 0.05). QoL was improved, using the two instruments: Parkinson's Disease Questionnaire-39 and 15D Quality of Life Instrument (p < 0.01). Adverse events were similar for both treatment strategies. Continuous intraduodenal infusion of the levodopa/carbidopa enteral gel as monotherapy is safe and clinically superior to a number of individually optimized combinations of conventional oral and subcutaneous medications in patients with motor fluctuations. Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mov Disord
                Journal ID (iso-abbrev): Mov. Disord
                Journal ID (publisher-id): mds
                Title: Movement Disorders
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 0885-3185
                ISSN (Electronic): 1531-8257
                Publication date (Print): April 2015
                Publication date (Electronic): 24 December 2014
                Volume: 30
                Issue: 4
                Pages: 500-509
                Affiliations
                [1 ]Center for Neurological Restoration, Cleveland Clinic Cleveland, Ohio, USA
                [2 ]University of Alabama at Birmingham Birmingham, Alabama, USA
                [3 ]Department of Neurology, University of South Florida Tampa, Florida, USA
                [4 ]University of Toronto Toronto, Ontario, Canada
                [5 ]Movement Disorders Unit, Westmead Hospital and Sydney Medical School Sydney, Australia
                [6 ]Charité-University Medicine Berlin Berlin, Germany
                [7 ]Keck/USC School of Medicine Los Angeles, California, USA
                [8 ]Klinikum-Bremerhaven, Bremerhaven, Germany and Skane University Hospital Lund, Sweden
                [9 ]Walton Center for Neurology and Neurosurgery Liverpool, United Kingdom
                [10 ]Kazan State Medical University Kazan, Russia
                [11 ]University of Montreal Montreal, Quebec, Canada
                [12 ]University of Alberta Edmonton, Alberta, Canada
                [13 ]AbbVie Inc., North Chicago Illinois, USA
                [14 ]University of Cincinnati Academic Health Center Cincinnati, Ohio, USA
                Author notes
                * Correspondence to: Dr. Hubert H. Fernandez, Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Avenue, U-2, Cleveland, OH 44195, USA; fernanh@ 123456ccf.org or Dr. David G. Standaert, Department of Neurology, 1719 6th Avenue South, CIRC 516, Birmingham, AL 35294, USA; dstandaert@ 123456uab.edu

                Funding agencies: This study was sponsored by AbbVie Inc. (North Chicago, IL, USA), which participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Funding for editorial and graphic support was provided by AbbVie Inc. to The Curry Rockefeller Group, LLC; medical writing assistance was provided by Michael Feirtag, Susan Kralian, PhD, Paul V. Shea, Jennifer Kuo, PharmD, and John Norwood of The Curry Rockefeller Group, LLC.

                Relevant conflicts of interest/financial disclosures: H.H.F. was a study investigator and has served as a consultant for AbbVie Inc. through a contract between AbbVie Inc. and Cleveland Clinic Foundation; he has not received any personal compensation from AbbVie Inc. D.G.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. R.A.H. was a study investigator for AbbVie Inc. and has received honoraria or payments for consulting, advisory services, or speaking services over the past 12 months from AbbVie Inc. A.E.L. was a study investigator for AbbVie Inc. and has received compensation from AbbVie Inc. for participating in scientific advisory boards. V.S.C.F. was a study investigator for, and has also received compensation from, AbbVie Inc. for participating in scientific advisory boards; AbbVie Inc. contributed to funding for a Parkinson's disease nurse specialist in the form of a grant to his institution. F.K. was a study investigator for, and has received compensation from, AbbVie Inc. for participating in scientific advisory boards and for serving as a lecturer. M.F.L. was a study investigator for AbbVie Inc. P.O. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for serving as a consultant and lecturer. M.S. was a study investigator in AbbVie Inc.-sponsored studies and has received compensation from AbbVie Inc. for participating in scientific advisory boards. E.Z.Y. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a lecturer. S.C. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards. O.S. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant and/or participating in scientific advisory boards. J.D., C.M.H., K.C., W.Z.R., and J.A.B. are employees of AbbVie Inc. A.J.E. was a study investigator for, and has received compensation from, AbbVie Inc. for serving as a consultant, lecturer, and/or participating in scientific advisory boards.

                Full financial disclosures and author roles may be found in the online version of this article.

                Article
                DOI: 10.1002/mds.26123
                PMC ID: 4674978
                PubMed ID: 25545465
                SO-VID: 85973b81-5271-49c5-a02a-6bff157e57f2
                Copyright © © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 28 August 2014
                Date revision received : 07 November 2014
                Date accepted : 18 November 2014
                Categories
                Subject: Research Articles

                ScienceOpen disciplines: Medicine
                Keywords: dyskinesia,infusion,levodopa-carbidopa intestinal gel,“off” time,percutaneous endoscopic gastrojejunostomy
                Data availability:
                ScienceOpen disciplines: Medicine
                Keywords: dyskinesia, infusion, levodopa-carbidopa intestinal gel, “off” time, percutaneous endoscopic gastrojejunostomy

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